DESCRIPTION: The modern Army is constrained by mitochondria. Mitochondria are the batteries of eukaryotic cells, and mitochondrially produced ATP is the energy that enables cognitive and physical performance in multicellular organisms. Mitochondrial insufficiency due to aging is directly correlated with reduced ATP production which in turn reduces physical and cognitive performance capabilities in humans. Highly qualified and very experienced soldiers regularly leave the Army because their physical and/or cognitive performance capabilities are significantly less than that of a 20 year old. Although people older than 42 are not eligible to join the Army, little has been done to reduce the effect of old mitochondria on DoD capabilities. At present, individuals attempt to counter their mitochondrial decline with frequent exercise and antioxidants, both of which are crude methods with limited effectiveness. A more precise methodology to stimulate mitochondrial energy production when needed would improve soldier cognitive and performance capabilities, and extend the time that soldiers remain fit for duty.

The past twenty years have seen a revolutionary breakthrough in understanding how mitochondria function. Human mitochondria are a network of approximately 2,000 proteins, exquisitely integrated into a larger network of approximately 100,000 cellular proteins, and again functionally integrated into a larger network of 3 billion cells. Sequence data is available for both the human nuclear and the mitochondrial genome. The biochemical basis of oxidative phosphorylation is well understood and genetic polymorphisms leading to altered energetics and performance capabilities are well documented. The scientific understanding and the technology to develop high throughput screening to identify and characterize compounds that improve neuronal adenosine triphosphate production is now feasible.

PHASE I: Design, construct, develop, and demonstrate the feasibility a high throughput system to identify compounds that increase adenosine triphosphate production in neurons.

PHASE II: Identify compounds that have stimulatory effects on neuronal adenosine triphosphate production and are capable of crossing the blood brain barrier. Identify and characterize the mechanism of action for lead compounds using genetics, genomics, bioinformatics, and/or biochemical approaches. Select one prototype compound for pharmaceutical production and FDA approval.

PHASE III: The "vision" is a warfighter force with improved energetic capabilities; this is analogous to replacing zinc carbon batteries with silver oxide batteries – more energy production capacity will enable the warfighter to sustain demanding cognitive or physical activities longer. The expectation is that the product coming out of this phase II research would transition directly to a small or large biotechnology or pharmaceutical company that would sell the product to warfighters. As vast numbers of civilians are old, substantial civilian interest is also anticipated.